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Purpose SimPET (www.sim-pet.org) is a free cloud-based platform for the generation of realistic brain positron emission tomography (PET) data. In this work, we introduce the key features of the platform. In addition, we validate the platform by performing a comparison between simulated healthy brain FDG-PET images and real healthy subject data for three commercial scanners (GE Advance NXi, GE Discovery ST, and Siemens Biograph mCT). Methods The platform provides a graphical user interface to a set of automatic scripts taking care of the code execution for the phantom generation, simulation (SimSET), and tomographic image reconstruction (STIR). We characterize the performance using activity and attenuation maps derived from PET/CT and MRI data of 25 healthy subjects acquired with a GE Discovery ST. We then use the created maps to generate synthetic data for the GE Discovery ST, the GE Advance NXi, and the Siemens Biograph mCT. The validation was carried out by evaluating Bland-Altman differences between real and simulated images for each scanner. In addition, SPM voxel-wise comparison was performed to highlight regional differences. Examples for amyloid PET and for the generation of ground-truth pathological patients are included. Results The platform can be efficiently used for generating realistic simulated FDG-PET images in a reasonable amount of time. The validation showed small differences between SimPET and acquired FDG-PET images, with errors below 10% for 98.09% (GE Discovery ST), 95.09% (GE Advance NXi), and 91.35% (Siemens Biograph mCT) of the voxels. Nevertheless, our SPM analysis showed significant regional differences between the simulated images and real healthy patients, and thus, the use of the platform for converting control subject databases between different scanners requires further investigation. Conclusions The presented platform can potentially allow scientists in clinical and research settings to perform MC simulation experiments without the need for high-end hardware or advanced computing knowledge and in a reasonable amount of time.

Metabolic reprogramming is considered hallmarks of cancer. Aerobic glycolysis in tumors cells has been well-known for almost a century, but specific factors that regulate lactate generation and the effects of lactate in both cancer cells and stroma are not yet well understood. In the present study using breast cancer cell lines, human primary cultures of breast tumors, and immune deficient murine models, we demonstrate that the POU1F1 transcription factor is functionally and clinically related to both metabolic reprogramming in breast cancer cells and fibroblasts activation. Mechanistically, we demonstrate that POU1F1 transcriptionally regulates the lactate dehydrogenase A (LDHA) gene. LDHA catalyzes pyruvate into lactate instead of leading into the tricarboxylic acid cycle. Lactate increases breast cancer cell proliferation, migration, and invasion. In addition, it activates normal-associated fibroblasts (NAFs) into cancer-associated fibroblasts (CAFs). Conversely, LDHA knockdown in breast cancer cells that overexpress POU1F1 decreases tumor volume and [18F]FDG uptake in tumor xenografts of mice. Clinically, POU1F1 and LDHA expression correlate with relapse- and metastasis-free survival. Our data indicate that POU1F1 induces a metabolic reprogramming through LDHA regulation in human breast tumor cells, modifying the phenotype of both cancer cells and fibroblasts to promote cancer progression This study was supported by FEDER/Ministerio de Ciencia, Innovación y Universidades- Agencia Estatal de Investigación-PGC2018-100776-B-I00 and from Conselleria de Cultura, Educación e Ordenacion Universitaria (GPC2014/001), AM-O was supported by an FPU grant (Ministerio de Educación—FPU14/00548) SI

Preclinical dynamic brain PET studies remain hampered by the limitations related to the measurement of the arterial input function (AIF). In this regard, the use of an arterial-venous shunt is a promising method for the generation of real-time AIFs, but its application in longitudinal studies is still impeded by the cumbersome surgeries and high failure rates. We studied the feasibility and reproducibility of double arterial-venous shunt strategies for conducting longitudinal PET studies with real-time AIFs in rats. We studied the feasibility of double arterial-venous shunts in rats in the right/left inguinal region and evaluated inter-animal and intra-animal AIF reproducibilities. Image-derived input function (IDIF) was also obtained for comparison. Dynamic brain FDG PET studies were conducted to estimate kinetic constants and Cerebral Metabolic Rate of Glucose (CMRglc) obtained from standard 2-tissue compartment (2TCM) and Patlak analysis. We showed that longitudinal AIFs from double arterial-venous shunts can be obtained with very high success rate of the surgeries (88 %). Our results provided highly reproducible AIF measurements with low inter-animal variabilities (11 %) and intra-animal variabilities (5–10 %) that were included into the kinetic models, such that longitudinal rate constants and CMRglc can be efficiently estimated without bias associated to the double shunt. Our results indicated that longitudinal IDIF can be also generated without bias along time but showing higher intra-animal uncertainties. We have demonstrated the feasibility and high reproducibility of conducting longitudinal AIF measurements and consequently accurate kinetic modeling using arterial shunt method.

Intravitreal injections are the standard procedure in the treatment of retinal pathologies, such as the administration of the anti-VEGF antibodies in age-related macular degeneration. The aim of this study is to evaluate the intraocular and blood pharmacokinetics after an intravitreal injection of 89Zr-labelled bevacizumab and 89Zr-labelled aflibercept in Sprague-Dawley rats using Positron Emission Tomography. First, both antibodies were radiolabelled to zirconium-89 with a maximum specific activity of 15 Mbq/mg for bevacizumab and 10 Mbq/mg for aflibercept. Four µL containing 1-1.2 Mq of 89Zr-labelled compound were injected into the vitreous through a 35 G needle. A microPET acquisition was carried out immediately after the injection and at different time points through a 12-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration above 95% for both agents. Both antibodies ocular curves followed a two-compartment model in which an intraocular elimination half-life of 16.44 h was found for 89Zr-bevacizumab and 4.51 h for 89Zr-aflibercept, considering the alpha phase as the elimination phase. Regarding the beta phase, a half-life of 3.23 days for 89Zr-bevacizumab and 4.69 days for 89Zr-aflibercept were observed. With regards to blood concentration, 89Zr-bevacizumab showed a blood half-life of 7.08 days, whereas 89Zr-aflibercept’s was 3.18 days, by a one-compartment model with first-order absorption kinetics. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis after intravitreal injection of aflibercept and bevacizumab in rats.

Resumen La inclusion de la PET 18F-FDG como biomarcador en los criterios de diagnostico clinico de enfermedades neurodegenerativas y su indicacion en el estudio precirugia en la epilepsia resistente a los farmacos permiten mejorar la especificidad del diagnostico. La interpretacion clasica de los estudios PET neurologicos se ha abordado de forma cualitativa, aunque en la ultima decada hemos sido testigos del auge en los sistemas de evaluacion cuantitativa. Este desarrollo tecnico es de vital importancia en la practica clinica, ya que mejora la especificidad y la reproducibilidad y reduce el efecto dependiente del observador derivado del analisis visual. Consideramos que es conveniente exponer la complejidad de las tecnicas de procesamiento de imagen empleadas, lo que permitira al especialista en Medicina Nuclear conocer sus ventajas e inconvenientes a la hora de incluirlas en la practica clinica diaria.

The inclusion of 18F-FDG PET as a biomarker in the diagnostic criteria of neurodegenerative diseases and its indication in the presurgical assessment for drug-resistant epilepsies allow to improve specificity of these diagnosis. The traditional interpretation of neurological PET studies has been performed qualitatively, although in the last decade, several quantitative evaluation methods have emerged. This technical development has become relevant in clinical practice, improving specificity, reproducibility and reducing the interrater reliability derived from visual analysis. In this article we update/review the main imaging processing techniques currently used. This may allow the Nuclear Medicine physician to know their advantages and disadvantages when including these procedures in daily clinical practice.

Purpose P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects. Methods Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed. Results At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers. Conclusion [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.

Background We aim to provide a systematic study of the impact of white matter (WM) spill-in on the calculation of standardized uptake value ratios (SUVRs) on Aβ-negative subjects, and we study the effect of including WM in the reference region as a compensation. In addition, different partial volume correction (PVC) methods are applied and evaluated. Methods We evaluated magnetic resonance imaging and 18F-AV-45 positron emission tomography data from 122 cognitively normal (CN) patients recruited at the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cortex SUVRs were obtained by using the cerebellar grey matter (CGM) (SUVRCGM) and the whole cerebellum (SUVRWC) as reference regions. The correlations between the different SUVRs and the WM uptake (WM-SUVRCGM) were studied in patients, and in a well-controlled framework based on Monte Carlo (MC) simulation. Activity maps for the MC simulation were derived from ADNI patients by using a voxel-wise iterative process (BrainViset). Ten WM uptakes covering the spectrum of WM values obtained from patient data were simulated for different patients. Three different PVC methods were tested (a) the regional voxel-based (RBV), (b) the iterative Yang (iY), and (c) a simplified analytical correction derived from our MC simulation. Results WM-SUVRCGM followed a normal distribution with an average of 1.79 and a standard deviation of 0.243 (13.6%). SUVRCGM was linearly correlated to WM-SUVRCGM (r = 0.82, linear fit slope = 0.28). SUVRWC was linearly correlated to WM-SUVRCGM (r = 0.64, linear fit slope = 0.13). Our MC results showed that these correlations are compatible with those produced by isolated spill-in effect (slopes of 0.23 and 0.11). The impact of the spill-in was mitigated by using PVC for SUVRCGM (slopes of 0.06 and 0.07 for iY and RBV), while SUVRWC showed a negative correlation with SUVRCGM after PVC. The proposed analytical correction also reduced the observed correlations when applied to patient data (r = 0.27 for SUVRCGM, r = 0.18 for SUVRWC). Conclusions There is a high correlation between WM uptake and the measured SUVR due to spill-in effect, and that this effect is reduced when including WM in the reference region. We also evaluated the performance of PVC, and we proposed an analytical correction that can be applied to preprocessed data.

It is unclear whether episodic memory is an appropriate descriptor of the cognitive continuum in mild cognitive impairment (MCI). Here, we investigated the ability of episodic memory to track cognitive changes in patients with MCI with biomarker evidence of Alzheimer's disease (AD). We examined 387 MCI amyloid-positive subjects, cognitively staged as "early" or "late" on the basis of episodic memory impairment. Cross-sectional and longitudinal comparisons between these 2 groups were performed for each amyloid, tau, and neurodegeneration (AT(N)) profile. Cross-sectional analyses indicate that "early" MCI represents a transitional phase between normal cognition and "late" MCI in the AD biomarker pathway. After adjusting by confounders and levels of A, T, and (N), "late" MCI progressed significantly faster than "early" MCI only in profiles with both abnormal amyloid and tau markers (A+T+(N)- p < 0.05, A+T+(N)+ p < 0.001). Episodic memory staging is useful for describing symptoms in prodromal AD and complements the AT(N) profiles. Our findings might have implications for the Numeric Clinical staging scheme of the National Institute on Aging and Alzheimer's Association research framework.

Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-&beta, cyclodextrin (HP&beta, CD) inclusion complexes&rsquo, formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HP&beta, CD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HP&beta, CD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HP&beta, CD and Liquifilm&reg, versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.

Background: Although many works have supported the utility of PET radiomics, several authors have raised concerns over the robustness and replicability of the results. This study aimed to perform a systematic review on the topic of PET radiomics and the used methodologies. Methods: PubMed was searched up to 15 October 2020. Original research articles based on human data specifying at least one tumor type and PET image were included, excluding those that apply only first-order statistics and those including fewer than 20 patients. Each publication, cancer type, objective and several methodological parameters (number of patients and features, validation approach, among other things) were extracted. Results: A total of 290 studies were included. Lung (28%) and head and neck (24%) were the most studied cancers. The most common objective was prognosis/treatment response (46%), followed by diagnosis/staging (21%), tumor characterization (18%) and technical evaluations (15%). The average number of patients included was 114 (median = 71; range 20–1419), and the average number of high-order features calculated per study was 31 (median = 26, range 1–286). Conclusions: PET radiomics is a promising field, but the number of patients in most publications is insufficient, and very few papers perform in-depth validations. The role of standardization initiatives will be crucial in the upcoming years This research was partially funded by DTS17/00138 (Instituto de Salud Carlos III) and ED431F 2017/04 project (GAIN-Xunta de Galicia) SI

The aim of this study was to fabricate novel self-supporting tacrolimus suppositories using semisolid extrusion 3-dimensional printing (3DP) and to investigate their efficacy in an experimental model of inflammatory bowel disease. Blends of Gelucire 44/14 and coconut oil were employed as lipid excipients to obtain suppository formulations with self-emulsifying properties, which were then tested in a TNBS (2,4,6-trinitrobenzenesulfonic acid) induced rat colitis model. Disease activity was monitored using PET/CT medical imaging, maximum standardized uptake values (SUVmax), a measure of tissue radiotracer accumulation rate, together with body weight changes and histological assessments, were used as inflammatory indices to monitor treatment efficacy. Following tacrolimus treatment, a significant reduction in SUVmax was observed on days 7 and 10 in the rat colon sections compared to non-treated animals. Histological analysis using Nancy index confirmed disease remission. Moreover, statistical analysis showed a positive correlation (R2 = 71.48%) between SUVmax values and weight changes over time. Overall, this study demonstrates the effectiveness of 3D printed tacrolimus suppositories to ameliorate colitis and highlights the utility of non-invasive PET/CT imaging to evaluate new therapies in the preclinical area.

Fungal keratitis is a severe infectious corneal disease. At present, no voriconazole ophthalmic formulations are approved by the FDA or EMA. This lack of therapeutic options leads to the reformulation of intravenous voriconazole preparations (VFEND®) by the hospital pharmacy departments to prepare the appropriate ophthalmic formulations (pharmacy compounding). However, the limited residence time of these formulations leads to an intensive treatment posology that may increase the occurrence of side effects. In the present study, two different hydrogels were developed and characterized in order to improve the voriconazole's ophthalmic solubility, permanence, and security. Voriconazole-cyclodextrin (HPβCD or HPɣCD) inclusion complexes in aqueous solutions were characterized by NMR and molecular modeling. Complexes were formed by encapsulation of voriconazole into the cyclodextrin's internal cavity which considerably increases its water solubility. Ocular safety was proven by ocular irritation studies. Permeability studies suggest both hydrogels have good corneal permeability. Furthermore, in vivo ocular permanence study by PET/CT showed a longer permanence time on the ocular surface (t1/2 = 58.91 ± 13.4 min and 96.28 ± 49.11 min for VZHAH and VZISH 0.65 respectively) compared to the voriconazole control formulation (VFEND® t1/2 = 32.27 ± 15.56 min). Results suggest these formulations are a good alternative for the treatment of fungal keratitis.

Background The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output. Methods Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings. Results Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering. Conclusions Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.

The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p ​= ​0.006), frontal (p ​= ​0.006), and parietal WMH (p ​= ​0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.

Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract, which two main types are Crohn’s disease and ulcerative colitis. It has multifactorial etiologies, being essential the use of animal models and disease activity measures to develop new therapies. With this aim, the use of animal models in combination with non-invasive molecular imaging can play an important role in the development of new treatments. In this study, IBD was induced in rats using 2,4,6-trinitrobenzenesulfonic acid (TNBS) and longitudinal [18F]FDG PET/CT scans were conducted to assess disease progression post-TNBS administration. Afterwards, [18F]FDG PET/CT scans were carried out after treatment with methylprednisolone to validate the model. In non-treated rats, SUVmax (Standardized Uptake Value) rapidly increased after IBD induction, being particularly significant (p In this study, we have performed the first longitudinal [18F]FDG PET/CT assessment of TNBS-induced IBD in rats, demonstrating the potential role of preclinical molecular imaging for the evaluation of new therapies in combination with IBD rat models.

Severe allergic ocular diseases as atopic keratoconjunctivitis can induce corneal damage due to inflammatory substances released from giant papillae. Tacrolimus eye drops are one of the current therapeutic alternatives for its treatment. This work is aimed at developing and characterizing a 0.03% tacrolimus ophthalmic formulation, which was introduced in three types of vehicles (BBS, PVA and Hyaluronic Acid). For this, we have performed in vitro (stability studies) and in vivo assays (corneal permanence time measured directly by Positron Emission Tomography) of three potential formulations. Next, the best formulation was selected, and its toxicological profile and clinical effectiveness have been evaluated. The biopermanence studies (direct measurements and PET/CT) showed that the formulations with PVA and Hyaluronic Acid present more retention time on the ocular surface of rats than PBS. From the stability study, we have determined that tacrolimus with PVA in cold storage is the best option. Tacrolimus with PVA has shown lower cytotoxicity than cyclosporine at early times. On the other hand, the pilot study performed has shown significant improvements in patients, with no noticeable adverse reactions. Based on stability, biopermanence, safety and clinical effectiveness studies, we concluded that tacrolimus-PVA eye drops are a suitable candidate for its clinical application in inflammatory ophthalmology diseases.

Fused deposition modelling (FDM) 3D printing (3DP) is a revolutionary technology with the potential to transform drug product design in both the pre-clinical and clinical arena. The objective of this pilot study was to explore the intestinal behaviour of four different polymer-based devices fabricated using FDM 3DP technology in rats. Small capsular devices of 8.6 mm in length and 2.65 mm in diameter were printed from polyvinyl alcohol-polyethylene glycol graft-copolymer (PVA-PEG copolymer, Kollicoat IR), hydroxypropylcellulose (HPC, Klucel), ethylcellulose (EC, Aqualon N7) and hypromellose acetate succinate (HPMCAS, Aquasolve-LG). A smaller sized device, 3.2 mm in length and 2.65 mm in diameter, was also prepared with HPMCAS to evaluate the cut off size of gastric emptying of solid formulations in rats. The devices were radiolabelled with Fluorodeoxyglucose (18F-FDG) and small animal positron emission tomography/computed tomography (microPET/CT) was used to track the movement and disintegration of the fabricated devices in the rats. The PVA-PEG copolymer and HPC devices disintegrated after 60min following oral administration. The EC structures did not disintegrate in the gastrointestinal tracts of the rats, whereas the HPMCAS-based systems disintegrated after 420 min. Interestingly, it was noted that the devices which remained intact over the course of the study had not emptied from the stomach of the rats. This was also the case with the smaller sized device. In summary, we report for the first time, the use of a microPET/CT imaging technique to evaluate the in vivo behaviour of 3D printed formulations. The manipulation of the 3D printed device design could be used to fabricate dosage forms of varying sizes and geometries with better gastric emptying characteristics suitable for rodent administration. The increased understanding of the capabilities of 3DP in dosage form design could, henceforth, accelerate pre-clinical testing of new drug candidates in animal models.

This study aims to determine whether PET textural features measured with a new dedicated breast PET scanner reflect biological characteristics of breast tumors. One hundred and thirty-nine breast tumors from 127 consecutive patients were included in this analysis. All of them underwent a 18F-FDG PET scan before treatment. Well-known PET quantitative parameters such as SUV m a x , SUV m e a n , metabolically active tumor volume (MATV) and total lesion glycolysis (TLG) were extracted. Together with these parameters, local, regional, and global heterogeneity descriptors, which included five textural features (TF), were computed. Immunohistochemical classification of breast cancer considered five subtypes: luminal A like (LA), luminal B like/HER2 − (LB −), luminal B like/HER2+ (LB+), HER2-positive-non-luminal (HER2pnl), and triple negative (TN). Associations between PET features and tumor characteristics were assessed using non-parametric hypothesis tests. Along with well-established associations, new correlations were found. HER2-positive tumors had significantly higher uptake (p 0.70) and presented different global and regional heterogeneity (p = 0.002, p = 0.016, respectively, AUCs < 0.70). Nine out of ten analyzed features were significantly associated with immunohistochemical subtype. Uptake was lower for LA tumors (p < 0.001) with AUCs ranging from 0.71 to 0.88 for each subgroup comparison. Heterogeneity metrics were significantly associated when comparing LA and LB − (p < 0.01), being regional heterogeneity metrics more discriminative than any other parameter (AUC = 0.80 compared to AUC = 0.71 for SUV). LB+ and HER2pnl tumors also showed more regional heterogeneity than LA tumors (AUCs = 0.79 and 0.84, respectively). After comparison with whole-body PET studies, we observed an overall improvement in the classification ability of both non-heterogeneity metrics and textural features. PET parameters extracted from high-resolution dedicated breast PET images showed new and stronger correlations with immunohistochemical factors and immunohistochemical subtype of breast cancer compared to whole-body PET.

Background Stuttering is a disorder in the rhythm of speech characterized by an involuntary repetition, prolongation, and cessation of sounds. Neurogenic acquired stuttering is a very rare disorder which could result from different conditions with the involvement of several brain locations. Case report A 16-year-old male presented to our Hospital with headache associated with blurred vision followed by right-sided facial and upper limb tingling, clumsiness of right arm, and a complete inability to formulate language which evolved in the next minutes into an intense speech disorder characterized by persistent stuttering. Urgent brain magnetic resonance imaging showed a prominence of venous vasculature in left hemisphere in susceptibility weighted imaging sequence. A fluorodeoxyglucose-positron emission tomography revealed a bilateral occipital, temporal, and parietal hypometabolism. With the suspicion of migraine aura, analgesic treatment was administered. Symptoms progressively resolved inside 10 hours. Five months later he experienced a similar episode. Conclusion This case report represents a diagnostic challenge and suggests the inclusion of stuttering within the neurological manifestations of higher cortical dysfunction that can be found as a result of migraine aura.

The aim of this study was to develop an accurate simulation and reconstruction model for the Philips Vereos digital whole-body PET/CT scanner. The model was developed using the SimSET Monte Carlo (MC) simulation code, storing all detected photons in SimSET list-mode (LM) format (history files). LM processing, binning and image reconstruction were performed using STIR recently added LM capabilities. In order to accurately process the listmode files generated by SimSET, a new interface between SimSET and STIR was developed. The performance of our MC model was evaluated using the NEMA NU2-2012 standard. Spatial resolution was in good agreement with published results(±12%). Count-rate performance was accurate overall, with NEC rates accurate for both low (32.5% vs. 31.7% at ≈ 5 KBq/mL), and high counts (146.2 kcps vs 153.4 at ≈ 55 KBq/mL), and consistent prompts for all the activity concentrations. LM-MLEM reconstruction including scatter and attenuation correction was performed to validate the SimSET-STIR developed interface.

International audience; Dopamine signaling is a crucial part of the brain reward system and can affect feeding behavior. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the CNS to regulate energy balance.

The objective of this preclinical in vivo study was to determine changes in vascular inflammatory biomarkers in systemic circulation after injection of lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg) in rats. Experimental periodontitis was induced by injections of Pg-LPS. Gingival soft and hard tissues changes were analysed by means of magnetic resonance imaging and micro computed tomography. Serum levels of interleukin (IL)-6, IL-10, pentraxin (PTX) 3, and soluble fragment of tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) were determined at baseline and 24 h, 7, 14, and 21 days after periodontal induction. Significant periodontal inflammation and alveolar bone loss were evident at the end of periodontal induction. Experimental periodontitis posed an acute systemic inflammatory response with increased serum levels of IL-6 and PTX3 at 24 h post-induction, followed by a significant overexpression of sTWEAK at 7 days. This inflammatory state was maintained until the end of the experiment (21 days). As expected, IL-10 serum levels were significantly lower during the follow-up compared to baseline concentrations. In the present animal model, experimental periodontitis is associated with increased systemic inflammation. Further studies are needed to confirm whether PTX3 and sTWEAK could be useful biomarkers to investigate potential mechanisms underlying the relationship between periodontitis and atherosclerotic vascular diseases.

Classical methodologies used in ocular pharmacokinetics studies have difficulties to obtain information about topical and intraocular distribution and clearance of drugs and formulations. This is associated with multiple factors related to ophthalmic physiology, as well as the complexity and invasiveness intrinsic to the sampling. Molecular imaging is a new diagnostic discipline for in vivo imaging, which is emerging and spreading rapidly. Recent developments in molecular imaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), allow obtaining reliable pharmacokinetic data, which can be translated into improving the permanence of the ophthalmic drugs in its action site, leading to dosage optimisation. They can be used to study either topical or intraocular administration. With these techniques it is possible to obtain real-time visualisation, localisation, characterisation and quantification of the compounds after their administration, all in a reliable, safe and non-invasive way. None of these novel techniques presents simultaneously high sensitivity and specificity, but it is possible to study biological procedures with the information provided when the techniques are combined. With the results obtained, it is possible to assume that molecular imaging techniques are postulated as a resource with great potential for the research and development of new drugs and ophthalmic delivery systems This work was partially supported by Instituto de Salud Carlos III-ISCIII (PI17/00940) and (RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) cofunded by FEDER. It was also supported by Fundación Española de Farmacia Hospitalaria (FEFH 18-19). A.F.-F. and C.M.G. acknowledges the support of ISCIII by research grants (JR18/00014 and CM18/00090). P.A. acknowledges the support of MICINN Ramon y Cajal RYC-2015-17430 (PA) SI

Celia’s encephalopathy (Progressive Encephalopathy with/without Lipodystrophy, PELD) is a childhood neurodegenerative disorder with a fatal prognosis before the age of 10, due to the variant c.985C>T in the BSCL2 gene that causes a cryptic splicing site leading to skipping of exon 7. For years, different authors have reported cases of congenital generalized lipodystrophy due to the variant c.974dupG in BSCL2 associated with neurological manifestations of variable severity, although some of them clearly superimposable to PELD. AIM: To identify the molecular mechanisms responsible for these neurological alterations in two patients with c.974dupG. SUBJECTS AND METHODS: Clinical characterization, biochemistry and neuroimaging studies of two girls carrying this variant. In silico analysis, PCR amplification and BSCL2 cDNA sequencing. BSCL2-201 transcript expression, which lacks exon 7, by qPCR in fibroblasts from the index case, from a healthy child as a control and from two patients with PELD, and in leukocytes from the index case and her parents. RESULTS: One of the children presented with a severe encephalopathy including a picture of intellectual deficiency, severe language impairment, myoclonic epilepsy and lipodystrophy as described in PELD, dying at 9 years and 9 months of age. The other 2-year-old patient showed incipient signs of neurological involvement. In silico and cDNA sequencing studies showed that variant c.974dupG gives rise to skipping of exon 7. The expression of BSCL2-201 in fibroblasts was significantly higher in the index case than in the healthy child, although less than in the case with homozygous PELD due to c.985C>T variant. The expression of this transcript was approximately half in the healthy carrier parents of this patient. CONCLUSIONS: The c.974dupG variant leads to the skipping of exon 7 of the BSCL2 gene, and is responsible for a variant of Celia’s encephalopathy, with variable phenotypic expression.

Inhaled administration of ethanol in the early stages of COVID-19 would favor its location on the initial replication sites, being able to reduce the progression of the disease and improving its prognosis. Before evaluating the efficacy and safety of this novel therapeutic strategy in humans, its characterization is required. The developed 65° ethanol formulation is stable at room temperature and protected from light for 15 days, maintaining its physicochemical and microbiological properties. Two oxygen flows have been tested for its administration (2 and 3 L/min) using an automated headspace gas chromatographic analysis technique (HS-GC-MS), with that of 2 L/min being the most appropriate one, ensuring the inhalation of an ethanol daily dose of 33.6 ± 3.6 mg/min and achieving more stable concentrations during the entire treatment (45 min). Under these conditions of administration, the formulation has proven to be safe, based on histological studies of the respiratory tracts and lungs of rats. On the other hand, these results are accompanied by the first preclinical molecular imaging study with radiolabeled ethanol administered by this route. The current ethanol formulation has received approval from the Spanish Agency of Medicines and Medical Devices for a phase II clinical trial for early-stage COVID-19 patients, which is currently in the recruitment phase (ALCOVID-19, EudraCT number: 2020-001760-29).

Purpose The aim of this work is to study the effect of physiological muscular uptake variations and statistical noise on tumor quantification in FDG-PET studies. Methods We designed a realistic framework based on simulated FDG-PET acquisitions from an anthropomorphic phantom that included different muscular uptake levels and three spherical lung lesions with diameters of 31, 21 and 9 mm. A distribution of muscular uptake levels was obtained from 136 patients remitted to our center for whole-body FDG-PET. Simulated FDG-PET acquisitions were obtained by using the Simulation System for Emission Tomography package (SimSET) Monte Carlo package. Simulated data was reconstructed by using an iterative Ordered Subset Expectation Maximization (OSEM) algorithm implemented in the Software for Tomographic Image Reconstruction (STIR) library. Tumor quantification was carried out by using estimations of SUVmax, SUV50 and SUVmean from different noise realizations, lung lesions and multiple muscular uptakes. Results Our analysis provided quantification variability values of 17–22% (SUVmax), 11–19% (SUV50) and 8–10% (SUVmean) when muscular uptake variations and statistical noise were included. Meanwhile, quantification variability due only to statistical noise was 7–8% (SUVmax), 3–7% (SUV50) and 1–2% (SUVmean) for large tumors (>20 mm) and 13% (SUVmax), 16% (SUV50) and 8% (SUVmean) for small tumors ( Conclusions Our study revealed that muscular uptake variations between patients who are totally relaxed should be considered as an uncertainty source of tumor quantification values.

Background The spinocerebellar ataxias (SCAs) form a clinically, genetically, and pathological heterogeneous group of autosomal-dominant degenerative diseases. In particular, SCA36 is characterized by a late-onset, slowly progressive cerebellar syndrome typically associated with sensorineural hearing loss. This study was aimed at analyzing the neurodegenerative process underlying SCA36 through fluorodeoxyglucose positron emission tomography (FDG-PET) and MRI scans. Methods Twenty SCA36 patients underwent a study consisting of FDG-PET and MRI scans. Clinical motor evaluation was performed through the Scale for the Assessment and Rating of Ataxia (SARA). FDG-PET was carried out using a voxel-by-voxel and region-of-interest analysis. MRI evaluation was based on visual inspection and volumetric analysis. Results SARA ranged from 0 to 24.5 (4 patients asymptomatic, 3 with unspecific symptoms, and 13 with cerebellar signs). FDG-PET revealed hypometabolism in the asymptomatic stage in the vermis and right cerebellar hemisphere. In the ataxic stage, hypometabolism spread to both cerebellar hemispheres and the brain stem. MRI was normal in asymptomatic and preataxic individuals and showed superior cerebellar vermis atrophy early in the ataxic stage, diffuse cerebellar atrophy some years into the disease course, and a pattern of olivopontocerebellar atrophy in the oldest patients. There was no significant cerebellar atrophy in patients younger than 50 years. Conclusions We present the first FDG-PET study of SCA36 and one of the largest neuroimaging study of SCAs. Our results revealed neuronal dysfunctions in the vermis and right cerebellar hemisphere as soon as a decade before the onset of motor symptoms. In the ataxic stage, dysfunctions spread to both hemispheres and the brain stem. © 2016 International Parkinson and Movement Disorder Society.

Purpose: The high mass density and low mobilities of charge carriers can cause important recombination in liquid-filled ionization chambers (LICs). Saturation correction methods have been proposed for LICs. Correction methods for pulsed irradiation are based on Boag equation. However, Boag equation assumes that the charge ionized by one pulse is fully collected before the arrival of the next pulse. This condition does not hold in many clinical beams where the pulse repetition period may be shorter than the charge collection time, causing overlapping between charge carriers ionized by different pulses, and Boag equation is not applicable there. In this work, the authors present an experimental and numerical characterization of collection efficiencies in LICs beyond the Boag limit, with overlapping between charge carriers ionized by different pulses. Methods: The authors have studied recombination in a LIC array for different dose-per-pulse, pulse repetition frequency, and polarization voltage values. Measurements were performed in a Truebeam Linac using FF and FFF modalities. Dose-per-pulse and pulse repetition frequency have been obtained by monitoring the target current with an oscilloscope. Experimental collection efficiencies have been obtained by using a combination of the two-dose-rate method and ratios to the readout of a reference chamber (CC13, IBA). The authors have also used numerical simulation to complement the experimental data. Results: The authors have found that overlap significantly increases recombination in LICs, as expected. However, the functional dependence of collection efficiencies on the dose-per-pulse does not change (a linear dependence has been observed in the near-saturation region for different degrees of overlapping, the same dependence observed in the nonoverlapping scenario). On the other hand, the dependence of collection efficiencies on the polarization voltage changes in the overlapping scenario and does not follow that of Boag equation, the reason being that changing the polarization voltage also affects the charge collection time, thus changing the amount of overlapping. Conclusions: These results have important consequences for saturation correction methods for LICs. On one hand, the two-dose-rate method, which relies on the functional dependence of the collection efficiencies on dose-per-pulse, can also be used in the overlapping situation, provided that the two measurements needed to feed the method are performed at the same pulse repetition frequency (monitor unit rate). This result opens the door to computing collection efficiencies in LICs in many clinical setups where charge overlap in the LIC exists. On the other hand, correction methods based on the voltage-dependence of Boag equation like the three-voltage method or the modified two-voltage method will not work in the overlapping scenario due to the different functional dependence of collection efficiencies on the polarization voltage.

Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance. This work was partially supported by the ISCIII (PI17/00940, RETICS Oftared, RD16/0008/0003 and RD12/0034/0017) cofunded by FEDER and by the Spanish Ministry of Science, Innovation and Universities (RTI2018-099597-B-100) SI

Magnetic resonance imaging (MRI) volumetric measures have become a standard tool for the detection of in-cipientAlzheimer'sDisease(AD)dementiainmildcognitiveimpairment(MCI).Focusedonprovidinganearlierand more accurate diagnosis, sophisticated MRI machine learning algorithms have been developed over therecentyears,mostofthemlearningtheirnon-diseasepatternsfromMCIthatremainedstableover2–3years.Inthis work, we analyzed whether these stable MCI over short-term periods are actually appropriate trainingexamples of non-disease patterns. To this aim, we compared the diagnosis of MCI patients at 2 and 5years offollow-up and investigated its impact on the predictive performance of baseline volumetric MRI measures pri-marily involved in AD, i.e., hippocampal and entorhinal cortex volumes. Predictive power was evaluated interms ofthe areaunder the ROCcurve(AUC), sensitivity,andspecificity inatrialsample of248 MCIpatientsfollowed-up over 5years. We further compared the sensitivity in those MCI that converted before 2years andthose that converted after 2years. Our results indicate that 23% of the stable MCI at 2years progressed in thenextthreeyearsandthatMRIvolumetricmeasuresaregoodpredictorsofconversiontoADdementiaevenatthemid-term, showing a better specificity and AUC as follow-up time increases. The combination of hippocampusand entorhinal cortex yielded an AUC that was significantly higher for the 5-year follow-up (AUC=73% at2yearsvs.AUC=84%at5years),aswellasforspecificity(56%vs.71%).Sensitivityshowedanon-significantslightdecrease(81%vs.78%).Remarkably,theperformanceofthismodelwascomparabletomachinelearningmodels at the same follow-up times. MRI correctly identified most of the patients that converted after 2years(with sensitivity>60%), and these patients showed a similar degree of abnormalities to those that convertedbefore 2years. This implies that most of the MCI patients that remained stable over short periods and subse-quentlyprogressedtoADdementiahadevidentatrophiesatbaseline.Therefore,machinelearningmodelsthatuse these patients to learn non-disease patterns are including an important fraction of patients with evidentpathological changes related to the disease, something that might result in reduced performance and lack ofbiological interpretability. This work was partially supported by the project PI16/01416(ISCIIIco-fundedFEDER) and RYC-2015/17430 (RamónyCajal,Pablo Aguiar). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI)(National Institutes of Health Grant U01AG024904) and DODADNI (Department of Defense award number W81XWH-12-2-0012) SI

Objective The aim of this investigation was to determine the circulating levels of amyloid beta (Aβ) peptides using the Porphyromonas gingivalis (Pg) lipopolysaccharide (LPS) model to induce periodontitis. Methods Experimental periodontitis was induced in 6 male Sprague-Dawley rats. Alveolar bone loss was measure by micro computed tomography. Serum concentrations of Aβ1–40 and Aβ1–42 prior to periodontal induction, at 24 h, 7, 14, and 21 days the last injection of Pg-LPS. Results The distance between the cemento-enamel junction and the bone crest (i.e., alveolar bone loss) was significantly higher at the end of periodontal induction compared to baseline (2.92 ± 0.29 mm vs. 3.8 ± 0.28 mm, P Conclusions Periodontitis induced Pg-LPS produced increased serum levels of Aβ peptides. Further studies are needed to confirm our results and to investigate the mechanisms by which periodontitis could be associated with an overexpression of Aβ.

In this paper we present a numerical model of initial recombination in media irradiated with high linear energy transfer (LET) ions, which relies on an amorphous track model of ionization of high LET particles, and diffusion, drift and recombination of ionized charge carriers. The model has fundamental applications for the study of recombination in non-polar liquids, as well as practical ones, like in modelling hadrontherapy dosimetry with ionization chambers. We have used it to study the response of liquid-filled ionization chambers to hadrontherapy beams: dependence of initial recombination on ion species, energy and applied external electric field.

Celia’s encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Age-related macular degeneration is the most common cause of vision loss in elderly people in developed countries. Nowadays, in clinical practice, three anti-VEGF drugs are commonly used (bevacizumab, aflibercept and ranibizumab), requiring repeated intravitreal injections. In order to minimise the number of injections, research on intravitreal drug delivery systems (DDSs) is needed. In this review, the DDSs developed up to date regarding intravitreal anti-VEGF drugs have been summarised, which include systems as hydrogels, liposomes, microparticles, nanoparticles or implants. Most of the studies have focused on the extended in vitro release behaviour of the developed DDSs, but data as antibody bioactivity, biocompatibility or in vivo stability is sometimes scarce. Moreover, as DDS development relies on in vivo pharmacokinetic analyses to evaluate the extended drug release, all the information regarding anti-VEGF intravitreal pharmacokinetics in different animal species have been compiled.

Inflammatory Bowel Disease (IBD) is a group of chronic disorders of the gastrointestinal tract, which two main types are Crohn's disease and ulcerative colitis. Although conventional therapeutic strategies have demonstrated to be effective in the IBD treatment, it is necessary to incorporate novel therapeutic agents that target other mechanisms involved in the pathogenesis of the disease, such as oxidative stress. For this reason, the efficacy in vivo of two antioxidant compounds, melatonin and resveratrol, has been investigated in an animal model of TNBS (2, 4, 6-trinitrobenzenesulfonic acid) induced colitis. PET/CT (Positron emission tomography/Computer Tomography) scans were performed to assess disease activity and evaluate treatment response. SUVmax (Standardized Uptake Value) values, body weight changes and histological evaluation were used as inflammatory indices to measure the efficacy of both treatments. SUVmax values increased rapidly after induction of colitis, but after the beginning of the treatment (day 3) a statistically significant decrease was observed on days 7 and 10 in treated animals compared to the non-treated group. This remission of the disease was also confirmed by histological analysis of the colon tissue using the Nancy histological index (p value < 0.05 for differences between non-treated and both groups of treated animals). Moreover, statistical analysis showed a correlation (R2 = 65.52%) between SUVmax values and weight changes throughout the treatment. Overall, this study demonstrates the potential of resveratrol, and melatonin in lower extent, as therapeutic agents in the IBD treatment.

In last years, sensitive hydrogels have become a breakthrough in ophthalmic pharmaceutical technology aimed at developing new strategies to increase the residence time of active substances. In a previous paper, we qualitatively demonstrated the capacity of a new ion sensitive hydrogel to increase the residence time. Nevertheless, the clearance of the gel from the ocular surface was not quantifiable with the used methodology. The aim of the present work was to use a well-established approach based on scintigraphy to quantitatively estimate the residence time of the previously proposed hydrogel. The rat corneal residence time of a topic ophthalmic formulation containing gellan gum and kappa carragenan (0.82% w/v) labeled with 99mTc-DTPA radiotracer was evaluated and compared with the residence of an aqueous solution. Ophthalmic safety studies such as eye irritation or passage through the cornea were also carried out. After 1.5 h of contact, 77% of the hydrogel remained in the ocular surface, presenting kinetics of disappearance one-phase decay and a half time of 262 min. We conclude that the novel ophthalmic hydrogel developed with kappa carrageenan and gellan gum remains for long periods of time on the corneal surface, presenting a drop that fits an exponential decay.

Structural Functional Synergistic Resolution Recovery (SFS-RR) is a technique that uses supplementary structural information from MR or CT to improve the spatial resolution of PET or SPECT images. This wavelet-based method may have a potential impact on the clinical decision-making of brain focal disorders such as refractory epilepsy, since it can produce images with better quantitative accuracy and enhanced detectability. In this work, a method for the iterative application of SFS-RR (iSFS-RR) was firstly developed and optimized in terms of convergence and input voxel size, and the corrected images were used for the diagnosis of 18 patients with refractory epilepsy. To this end, PET/MR images were clinically evaluated through visual inspection, atlas-based asymmetry indices (AIs) and SPM (Statistical Parametric Mapping) analysis, using uncorrected images and images corrected with SFS-RR and iSFS-RR. Our results showed that the sensitivity can be increased from 78% for uncorrected images, to 84% for SFS-RR and 94% for the proposed iSFS-RR. Thus, the proposed methodology has demonstrated the potential to improve the management of refractory epilepsy patients in the clinical routine.

The last recommendations of the International Commission on Radiological Protection for eye lens dose suggest an important reduction on the radiation limits associated with early and late tissue reactions. The aim of this work is to quantify and optimize the eye lens dose associated to nurse staff during positron emission tomography (PET) procedures. PET is one of the most important diagnostic methods of oncological and neurological cancer disease involving an important number of workers exposed to the high energy isotope F-18. We characterize the relevant stages as preparation and administration of monodose syringes in terms of occupational dose. A direct reading silicon dosimeter was used to measure the lens dose to staff. The highest dose of radiation was observed during preparation of the fluorodesoxyglucose (FDG) syringes. By optimizing a suitable vials' distribution of FDG we find an important reduction in occupational doses. Extrapolation of our data to other clinical scenarios indicates that, depending on the work load and/or syringes activity, safety limits of the dose might be exceeded.

Current guidelines for brain PET imaging advice against the injection of diazepam prior to brain FDG-PET examination in order to avoid possible interactions of benzodiazepines with the radiotracer uptake. Nevertheless, many patients undergoing PET studies are likely to be under chronic treatment with benzodiazepines, for example due to the use of different medications such as sleeping pills. Animal studies may provide an extensive and accurate estimation of the effect of benzodiazepines on brain metabolism in a well-defined and controlled framework.This study aims at evaluating the impact of benzodiazepines on brain FDG uptake after single-dose administration and chronic treatment in rats.Twelve Sprague-Dawley healthy rats were randomly divided into two groups, one treated with diazepam and the other used as control group. Both groups underwent PET/CT examinations after single-dose and chronic administration of diazepam (treated) or saline (controls) during twenty-eight days. Different atlas-based quantification methods were used to explore differences on the total uptake and uptake patterns of FDG between both groups.Our analysis revealed a significant reduction of global FDG uptake after acute (-16.2%) and chronic (-23.2%) administration of diazepam. Moreover, a strong trend pointing to differences between acute and chronic administrations (p0.08) was also observed. Uptake levels returned to normal after interrupting the administration of diazepam. On the other hand, patterns of FDG uptake were not affected by the administration of diazepam.The administration of diazepam causes a progressive decrease of the FDG global uptake in the rat brain, but it does not change local patterns within the brain. Under these conditions, visual assessment and quantification methods based on regional differences such as asymmetry indexes or SPM statistical analysis would still be valid when administrating this medication.

The aim of this work was to obtain a set of parameters to be applied in [123I]FP-CIT SPECT reconstruction in order to minimize the error between standardized and true values of the specific uptake ratio (SUR) in dopaminergic neurotransmission SPECT studies. To this end, Monte Carlo simulation was used to generate a database of 1380 projection data-sets from 23 subjects, including normal cases and a variety of pathologies. Studies were reconstructed using filtered back projection (FBP) with attenuation correction and ordered subset expectation maximization (OSEM) with correction for different degradations (attenuation, scatter and PSF). Reconstruction parameters to be optimized were the cut-off frequency of a 2D Butterworth pre-filter in FBP, and the number of iterations and the full width at Half maximum of a 3D Gaussian post-filter in OSEM. Reconstructed images were quantified using regions of interest (ROIs) derived from Magnetic Resonance scans and from the Automated Anatomical Labeling map. Results were standardized by applying a simple linear regression line obtained from the entire patient dataset. Our findings show that we can obtain a set of optimal parameters for each reconstruction strategy. The accuracy of the standardized SUR increases when the reconstruction method includes more corrections. The use of generic ROIs instead of subject-specific ROIs adds significant inaccuracies. Thus, after reconstruction with OSEM and correction for all degradations, subject-specific ROIs led to errors between standardized and true SUR values in the range [-0.5, +0.5] in 87% and 92% of the cases for caudate and putamen, respectively. These percentages dropped to 75% and 88% when the generic ROIs were used.

The resistance of hypoxic cells to radiation, due to the oxygen dependence of radiosensitivity, is well known and must be taken into account to accurately calculate the radiation induced cell death. A proper modelling of the response of tumours to radiation requires deriving the distribution of oxygen at a microscopic scale. This usually involves solving the reaction-diffusion equation in tumour voxels using a vascularization distribution model. Moreover, re-oxygenation arises during the course of radiotherapy, one reason being the increase of available oxygen caused by cell killing, which can turn hypoxic tumours into oxic. In this work we study the effect of cell death kinetics in tumour oxygenation modelling, analysing how it affects the timing of re-oxygenation, surviving fraction and tumour control. Two models of cell death are compared, an instantaneous cell killing, mimicking early apoptosis, and a delayed cell death scenario in which cells can die shortly after being damaged, as well as long after irradiation. For each of these scenarios, the decrease in oxygen consumption due to cell death can be computed globally (macroscopic voxel average) or locally (microscopic). A re-oxygenation model already used in the literature, the so called full re-oxygenation, is also considered. The impact of cell death kinetics and re-oxygenation on tumour responses is illustrated for two radiotherapy fractionation schemes: a conventional schedule, and a hypofractionated treatment. The results show large differences in the doses needed to achieve 50% tumour control for the investigated cell death models. Moreover, the models affect the tumour responses differently depending on the treatment schedule. This corroborates the complex nature of re-oxygenation, showing the need to take into account the kinetics of cell death in radiation response models.

Subtraction of Ictal SPECT Co-registered to MRI (SISCOM) is an imaging technique used to localize the epileptogenic focus in patients with intractable partial epilepsy. The aim of this study was to determine the accuracy of registration algorithms involved in SISCOM analysis using FocusDET, a new user-friendly application. To this end, Monte Carlo simulation was employed to generate realistic SPECT studies. Simulated sinograms were reconstructed by using the Filtered BackProjection (FBP) algorithm and an Ordered Subsets Expectation Maximization (OSEM) reconstruction method that included compensation for all degradations. Registration errors in SPECT-SPECT and SPECT-MRI registration were evaluated by comparing the theoretical and actual transforms. Patient studies with well-localized epilepsy were also included in the registration assessment. Global registration errors including SPECT-SPECT and SPECT-MRI registration errors were less than 1.2 mm on average, exceeding the voxel size (3.32 mm) of SPECT studies in no case. Although images reconstructed using OSEM led to lower registration errors than images reconstructed with FBP, differences after using OSEM or FBP in reconstruction were less than 0.2 mm on average. This indicates that correction for degradations does not play a major role in the SISCOM process, thereby facilitating the application of the methodology in centers where OSEM is not implemented with correction of all degradations. These findings together with those obtained by clinicians from patients via MRI, interictal and ictal SPECT and video-EEG, show that FocusDET is a robust application for performing SISCOM analysis in clinical practice.